Featured Research

Scientists Identify A New Kind Of Genetic Problem In Muscular Dystrophy

Date:

August 12, 2002

Source:

NIH/National Institute Of Neurological Disorders And Stroke

Summary:

A newly identified genetic problem underlies a common neuromuscular disorder called facioscapulohumeral muscular dystrophy (FSHD), scientists say. In a new study, they show that deletion of repetitive DNA sequences in people with this disorder allows nearby genes to go into overdrive. The finding solves a decade-old riddle about the cause of this disorder and may ultimately lead to the first effective treatments.

Share This

A newly identified genetic problem underlies a common neuromuscular disorder called facioscapulohumeral muscular dystrophy (FSHD), scientists say. In a new study, they show that deletion of repetitive DNA sequences in people with this disorder allows nearby genes to go into overdrive. The finding solves a decade-old riddle about the cause of this disorder and may ultimately lead to the first effective treatments.

Related Articles

The study found that abnormally short strings of repeated DNA sequences on chromosome 4 interfere with the function of a protein complex that controls nearby genes. This leads to over-activity of several genes that may play a role in the disorder. This type of genetic problem has never before been identified in a human disease. The study was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in the August 9, 2002, issue of Cell.

Scientists first linked the short strings of DNA in this region to FSHD in 1992. People with FSHD typically have fewer than 11 copies of this nucleic acid sequence, called D4Z4, due to a deletion of part of the chromosome. In contrast, people without the disorder usually carry between 11 and 150 copies of the sequence. People with a very small number of copies (three or fewer) have severe disease symptoms that begin in childhood, while those with several more copies typically have milder symptoms that begin in the teens or early adulthood. However, until now, researchers have been unable to determine exactly how the number of DNA sequences influences the disease.

FSHD is the third most common inherited neuromuscular disorder, affecting one in every 20,000 people (only Duchenne muscular dystrophy and myotonic dystrophy are more common). People with FSHD have progressive muscle degeneration that primarily affects the face, shoulder blades, and upper arms, although other muscles also deteriorate. Despite intensive efforts, researchers have been unable to identify any genes that are altered in this disorder.

In the new study, Rossella Tupler, M.D., Ph.D., of the University of Massachusetts Medical School in Worcester and the Universita' degli Studi di Pavia in Pavia, Italy, and colleagues studied human muscle tissue from healthy individuals and from people with FSHD as well as several other types of muscular dystrophy. They analyzed the expression of three genes located near the D4Z4 region and found that activity of all three genes was elevated in the muscle from FSHD patients compared to that of other people.

The researchers also analyzed the interaction between the D4Z4 sequence and proteins present in the nucleus of the cell. They found that one part of the sequence binds to a protein complex that normally suppresses gene activity. Having fewer than 11 copies of D4Z4 reduced the number of functional protein complexes, which in turn reduced control of genes from nearby parts of the chromosome.

"This breakthrough is important scientifically, as it teaches us about novel ways genes can influence disease, which will someday help not only those people who suffer from FSHD, but hopefully, others as well," says Katrina Gwinn-Hardy, M.D., a program director at NINDS.

The researchers do not know which of the overactive chromosome 4 genes is responsible for the symptoms of FSHD. One of the genes they considered, called ANT1, triggers cell death when it is too active. Therefore it may be responsible for the progressive loss of muscle cells in this disorder. However, FSHD is a complex disease, and other genes or environmental factors also may play a role.

"These findings have specific implications for the disease, and general implications for genetic research," says Dr. Tupler. Knowing how the D4Z4 deletions affect nearby genes points to new strategies for treating the disorder. For example, researchers might be able to find a way to mimic the effect of the protein complex that goes awry in this disorder, thereby reducing the activity of all the affected genes. If a specific gene that causes the disorder can be identified, researchers also might be able to slow or halt that gene's activity with drugs or other treatments.

While most people with FSHD have D4Z4 deletions, about 5 to 10 percent do not. These people may have mutations that affect the protein complex, Dr. Tupler says. Researchers have also identified people without FSHD who are missing the entire D4Z4 region and several nearby genes. This suggests that an abnormal D4Z4 region somehow creates havoc in muscle cells and/or that the nearby genes are necessary for development of the disease.

The findings also suggest that repetitive DNA sequences play a previously unsuspected role in human disease by influencing gene activity, Dr. Tupler says. About 40 percent of the human genome is comprised of these repetitive sequences, and they might play a role in several other human disorders. For example, certain variations in repetitive DNA sequences near the insulin gene in Type 1 diabetes have been linked to insulin levels and birth size. Other DNA repeats have been associated with bladder cancer. Studies of sequences like these could lead to a much better understanding of how gene activity is regulated, Dr. Tupler suggests.

Scientists can now focus on identifying which genes on chromosome 4 contribute to FSHD and how to regulate the gene activity, says Dr. Tupler. "Hopefully, other researchers will help with that," she adds.

The NINDS is a component of the National Institutes of Health in Bethesda, Maryland, and is the nation's primary supporter of biomedical research on the brain and nervous system.

NIH/National Institute Of Neurological Disorders And Stroke. (2002, August 12). Scientists Identify A New Kind Of Genetic Problem In Muscular Dystrophy. ScienceDaily. Retrieved March 31, 2015 from www.sciencedaily.com/releases/2002/08/020812065737.htm

Mar. 31, 2015  Increasing state alcohol taxes could prevent thousands of deaths a year from car crashes, say researchers, who found alcohol-related motor vehicle crashes decreased after taxes on beer, wine and ... full story

Mar. 31, 2015  Alcoholism takes a toll on every aspect of a person's life, including skin problems. Now, a new research report helps explain why this happens and what might be done to address it. "The clinical ... full story

Mar. 31, 2015  A new population of 'memory' immune cells has been discovered by scientists, throwing light on what the body does when it sees a microbe for the second time. This insight, and others like it, will ... full story

Mar. 31, 2015  Coronary heart disease and stroke, two of the leading causes of death in the United States, are diseases associated with heightened platelet reactivity. A new study in humans suggests an underlying ... full story

Mar. 31, 2015  A new study had researchers seeking answers to why the therapeutic benefit afforded by SSRIs was so limited in children and teenagers. If researchers can uncover the biological mechanisms preventing ... full story

Mar. 31, 2015  A drug being developed to treat osteoporosis may also be useful for treating osteogenesis imperfecta or brittle bone disease, a rare but potentially debilitating bone disorder that that is present ... full story

Mar. 31, 2015  It is possible to quantify and classify the effects of different diseases on the activity of intestinal bacteria, new research demonstrates for the first time. Human intestinal flora, known as ... full story

Mar. 31, 2015  During prenatal development, the brains of most animals, including humans, develop specifically male or female characteristics. But scientists have known little about the details of how this ... full story

Mar. 31, 2015  A history of depression may put women at risk for developing diabetes during pregnancy, according to research. This study also pointed to how common depression is during pregnancy and the need for ... full story

Featured Videos

Solitair Device Aims to Takes Guesswork out of Sun Safety

Reuters - Innovations Video Online (Mar. 31, 2015)  The Solitair device aims to take the confusion out of how much sunlight we should expose our skin to. Small enough to be worn as a tie or hair clip, it monitors the user&apos;s sun exposure by taking into account their skin pigment, location and schedule. Matthew Stock reports.
Video provided by Reuters

Soda, Salt and Sugar: The Next Generation of Taxes

Washington Post (Mar. 30, 2015)  Denisa Livingston, a health advocate for the Dinι Community Advocacy Alliance, and the Post&apos;s Abby Phillip discuss efforts around the country to make unhealthy food choices hurt your wallet as much as your waistline.
Video provided by Washington Post

S. Leone in New Anti-Ebola Lockdown

AFP (Mar. 28, 2015)  Sierra Leone imposed a three-day nationwide lockdown Friday for the second time in six months in a bid to prevent a resurgence of the deadly Ebola virus. Duration: 01:17
Video provided by AFP

Related Stories

Sep. 14, 2014  A potential way to treat muscular dystrophy directly targets muscle repair instead of the underlying genetic defect that usually leads to the disease, researchers say. Muscular dystrophies are a ... full story

Aug. 28, 2014  An animal research model has been developed for facioscapulohumeral muscular dystrophy (FSHD) to be used for muscle regeneration research as well as studies of the effectiveness of potential ... full story

Jan. 27, 2014  Researchers recently announced study findings showing the successful development of a humanized preclinical model for facioscapulohumeral muscular dystrophy, providing scientists with a much needed ... full story

Mar. 5, 2012  Scientists have used a revolutionary new DNA-reading technology for a research project that could lead to correct genetic diagnosis for muscle-wasting diseases. The technique could be used to offer ... full story

Jan. 12, 2012  Continuing a series of groundbreaking discoveries begun in 2010 about the genetic causes of the third most common form of inherited muscular dystrophy, scientists have identified the genes and ... full story

ScienceDaily features breaking news and videos about the latest discoveries in health, technology, the environment, and more -- from major news services and leading universities, scientific journals, and research organizations.